Neointimal fibroproliferation is the pathological process that underlies restenosis after angioplasty. The pathophysiological events resulting in neointimal proliferation can be divided into three stages: the acute initiating phase in response to injury, the intermediate phase of smooth muscle migration and proliferation, and the chronic perpetuating phase of neointimal proliferation. The purpose of this research will be to elucidate basic mechanisms involved in the initiating phase of neointimal fibroproliferation following mechanically-induced endothelial injury resulting from coronary artery angioplasty in canine models with and without intrinsic coronary atherosclerosis. Based on mechanistic insights gained, we hope to develop protective therapies that prevent neointimal fibroproliferation following balloon angioplasty. Cell culture tissues and chronically instrumented canine models with and without native coronary artery atherosclerosis will be used to rest the following hypotheses: (a) Platelet aggregation, platelet-vessel wall interaction and the release f platelet-derived products are necessary for the development of neointimal fibroproliferation; (b) Platelet-derived vasoactive substances (thromboxane A2 and serotonin) and vessel wall- derived vasoactive substances (angiotensin II) interact synergistically with other locally generated growth factors to initiate the process of neointimal fibroproliferation and restenosis that occurs after coronary artery angioplasty; (c) Fibroblast growth factor and its receptors play a role in the neointimal proliferation that occurs following balloon angioplasty, and they are increased following endothelial injury from coronary artery angioplasty in dogs with and without coronary artery atherosclerosis; and (d) An inhibitor of smooth muscle cell proliferation, saporin, linked to fibroblast growth factor or to specific monoclonal antibodies directed at fibroblast growth factor receptors, in conjunction with inhibitors of platelet aggregation (e.g. antagonists of thromboxane A2 and serotonin) markedly attenuates neointimal proliferation following endothelial injury induced by angioplasty.